Giuseppe
Emeritus
[Source: American Journal of Respiratory Cell and Molecular Biology, full text: (LINK). Abstract, edited.]
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Glutathione Peroxidase-1 Reduces Influenza A Virus?Induced Lung Inflammation
Selcuk Yatmaz<SUP>1</SUP>, Huei Jiunn Seow<SUP>1</SUP>, Rosa C. Gualano<SUP>1</SUP>, Zi Xin Wong<SUP>1</SUP>, John Stambas<SUP>2</SUP>, Stavros Selemidis<SUP>3</SUP>, Peter J. Crack<SUP>1</SUP>, Steven Bozinovski<SUP>1</SUP>, Gary P. Anderson<SUP>1</SUP> and Ross Vlahos<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>1</SUP>Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia <SUP>2</SUP>School of Medicine, Deakin University, Waurn Ponds, Australia; and <SUP>3</SUP>Department of Pharmacology, Monash University, Clayton, Australia
Correspondence and requests for reprints should be addressed to Ross Vlahos, Ph.D., Department of Pharmacology, The University of Melbourne, Parkville, VIC, 3010 Australia. E-mail: rossv@unimelb.edu.au
Abstract
Oxidative stress caused by excessive reactive oxygen species production is implicated in influenza A virus?induced lung disease. Glutathione peroxidase (GPx)-1 is an antioxidant enzyme that may protect lungs from such damage. The objective of this study was to determine if GPx-1 protects the lung against influenza A virus?induced lung inflammation in vivo. Male wild-type (WT) or GPx-1<SUP>−/−</SUP> mice were inoculated with HKx31 (H3N2, 1 ? 10<SUP>4</SUP> plaque-forming units), and bronchoalveolar lavage fluid (BALF)/lung compartments were analyzed on Days 3 and 7 after infection for inflammatory marker expression, histology, and viral titer. WT mice infected with HKx31 had significantly more BALF total cells, macrophages, neutrophils, and lymphocytes at Days 3 and 7 compared with naive WT animals (n = 5?8; P < 0.05). However, infected GPx-1<SUP>−/−</SUP> mice had significantly more BALF inflammation, which included more total cells, macrophages, and neutrophils, compared with WT mice, and this was abolished by treatment with the GPx mimetic ebselen. BALF inflammation persisted in GPx-1<SUP>−/−</SUP> mice on Day 10 after infection, and GPx-1<SUP>−/−</SUP> mice had significantly more influenza-specific CD8<SUP>+</SUP> T cells in spleen compared with WT mice (n = 3?4; P < 0.05). Infected GPx-1<SUP>−/−</SUP> mice had greater peribronchial and parenchymal inflammation than WT mice, and viral titer was significantly reduced in GPx-1<SUP>−/−</SUP> mice at Day 3 (n = 5; P < 0.05). Gene expression analysis revealed that infected GPx-1<SUP>−/−</SUP> mice had higher whole lung TNF-α, macrophage inflammatory protein (MIP)-1α, MIP-2, KC, and matrix metalloproteinase (MMP)-12 mRNA compared with infected WT mice. GPx-1<SUP>−/−</SUP> mice had more MIP-2 protein in BALF at Day 3 and more active MMP-9 protease in BALF at Days 3 and 7 than WT mice. These data indicate that GPx-1 reduces influenza A virus?induced lung inflammation.
oxidative stress - reactive oxygen species - hydrogen peroxide ? HKx31 ? ebselen ? antioxidants
Footnotes
This work was supported by the National Health and Medical Research Council of Australia and the Australian Research Council.
Author Contributions: R.V. and S.B. were involved in the conception and design of the study. S.Y., H.J.S., R.C.G., Z.X.W., S.S., and R.V. were involved in acquisition of the data. R.V., S.Y., R.C.G., S.B., S.S., J.S., P.J.C., and G.P.A. analyzed and interpreted the data. R.V., S.Y., S.B., R.C.G., S.S., and G.P.A. wrote the article.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1165/rcmb.2011-0345OC on September 20, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
Received September 29, 2011.
Accepted August 23, 2012.
Copyright ? 2013 by the American Thoracic Society
-Selcuk Yatmaz<SUP>1</SUP>, Huei Jiunn Seow<SUP>1</SUP>, Rosa C. Gualano<SUP>1</SUP>, Zi Xin Wong<SUP>1</SUP>, John Stambas<SUP>2</SUP>, Stavros Selemidis<SUP>3</SUP>, Peter J. Crack<SUP>1</SUP>, Steven Bozinovski<SUP>1</SUP>, Gary P. Anderson<SUP>1</SUP> and Ross Vlahos<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>1</SUP>Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia <SUP>2</SUP>School of Medicine, Deakin University, Waurn Ponds, Australia; and <SUP>3</SUP>Department of Pharmacology, Monash University, Clayton, Australia
Correspondence and requests for reprints should be addressed to Ross Vlahos, Ph.D., Department of Pharmacology, The University of Melbourne, Parkville, VIC, 3010 Australia. E-mail: rossv@unimelb.edu.au
Abstract
Oxidative stress caused by excessive reactive oxygen species production is implicated in influenza A virus?induced lung disease. Glutathione peroxidase (GPx)-1 is an antioxidant enzyme that may protect lungs from such damage. The objective of this study was to determine if GPx-1 protects the lung against influenza A virus?induced lung inflammation in vivo. Male wild-type (WT) or GPx-1<SUP>−/−</SUP> mice were inoculated with HKx31 (H3N2, 1 ? 10<SUP>4</SUP> plaque-forming units), and bronchoalveolar lavage fluid (BALF)/lung compartments were analyzed on Days 3 and 7 after infection for inflammatory marker expression, histology, and viral titer. WT mice infected with HKx31 had significantly more BALF total cells, macrophages, neutrophils, and lymphocytes at Days 3 and 7 compared with naive WT animals (n = 5?8; P < 0.05). However, infected GPx-1<SUP>−/−</SUP> mice had significantly more BALF inflammation, which included more total cells, macrophages, and neutrophils, compared with WT mice, and this was abolished by treatment with the GPx mimetic ebselen. BALF inflammation persisted in GPx-1<SUP>−/−</SUP> mice on Day 10 after infection, and GPx-1<SUP>−/−</SUP> mice had significantly more influenza-specific CD8<SUP>+</SUP> T cells in spleen compared with WT mice (n = 3?4; P < 0.05). Infected GPx-1<SUP>−/−</SUP> mice had greater peribronchial and parenchymal inflammation than WT mice, and viral titer was significantly reduced in GPx-1<SUP>−/−</SUP> mice at Day 3 (n = 5; P < 0.05). Gene expression analysis revealed that infected GPx-1<SUP>−/−</SUP> mice had higher whole lung TNF-α, macrophage inflammatory protein (MIP)-1α, MIP-2, KC, and matrix metalloproteinase (MMP)-12 mRNA compared with infected WT mice. GPx-1<SUP>−/−</SUP> mice had more MIP-2 protein in BALF at Day 3 and more active MMP-9 protease in BALF at Days 3 and 7 than WT mice. These data indicate that GPx-1 reduces influenza A virus?induced lung inflammation.
oxidative stress - reactive oxygen species - hydrogen peroxide ? HKx31 ? ebselen ? antioxidants
Footnotes
This work was supported by the National Health and Medical Research Council of Australia and the Australian Research Council.
Author Contributions: R.V. and S.B. were involved in the conception and design of the study. S.Y., H.J.S., R.C.G., Z.X.W., S.S., and R.V. were involved in acquisition of the data. R.V., S.Y., R.C.G., S.B., S.S., J.S., P.J.C., and G.P.A. analyzed and interpreted the data. R.V., S.Y., S.B., R.C.G., S.S., and G.P.A. wrote the article.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1165/rcmb.2011-0345OC on September 20, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
Received September 29, 2011.
Accepted August 23, 2012.
Copyright ? 2013 by the American Thoracic Society
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